I. Polyamines
Polyamine biochemistry is believed to be intimately associated with cell growth and proliferation. This is, in part, because interference with polyamine biosynthesis and/or function can lead to cell growth inhibition or cell death (Tabor et al, Ann. Rev. Biochem., 53:749-790 (1984); and Pegg, Cancer Res., 48:759-774 (1988)). Further, rapidly growing tissues, such as tumors, have a high demand for polyamines, and accumulate polyamines effectively (Seppanen, Acta Chem. Scand. B., 35:731-736 (1981)).
In addition, spermine and other polyamines bind avidly to DNA (Tabor et al, supra), and hence can be used to target DNA.
Thus, the polyamine homeostatic system has become a target for the design of new agents that might be concentrated in neoplastic cells and tissues via the polyamine transporter, and interact selectively with DNA.
II. Alkylating Agents
A major class of anti-cancer drugs are the alkylating agents. Alkylating agents are thought to exert tumor cell killing potency by their ability to bind and form adducts with DNA (Meltzer, J. Cancer Res. Clin. Oncol., 112:210 (1986); and Farmer, Pharmacol. Ther., 35:301 (1987)).
Aziridine (ethylenimine) is a ring-strained alkylating functional group that reacts covalently with cellular nucleophiles, such as DNA (Hemminki et al, Acta Pharmacol. Toxicol., 53:421-428 (1983); and Musser et al, Chem. Res. Toxicol., 5:95-99 (1992)). Examples of known aziridine-containing anti-cancer agents include thiotepa, mitomycin C, and diazaquone.
III. Putrescine-Based Anti-Cancer Agents
The naturally occurring polyamines, which include putrescine, spermidine and spermine, have been chemically modified to yield a number of agents that perturb polyamine biosynthesis, transport, or function (Porter et al, Cancer Res., 47: 2821-2825 (1987); and Heston et al, Biochem. Pharmacol., 36:1849-1852 (1987)). For example, replacement of the two amino groups of putrescine with aziridines produces the analogue, N,N'-bisaziridinyl-1,4-diaminobutane.
However, N,N'-bisaziridinyl-1,4-diaminobutane is a much less effective inhibitor of putrescine uptake than N-(4-aminobutyl)aziridine (Piper et al, J. Med. Chem., 12:236-243 (1969)), wherein a single amino group of putrescine has been replaced with aziridine (O'Sullivan et al, Biochem. Pharmacol., 41:1839-1848 (1991)).
N-(4-aminobutyl)aziridine has been shown to be cytotoxic against prostatic carcinoma cells (Heston et al, supra).
However, N-(4-aminobutyl)aziridine is disadvantageous because the butyl amine chain is less effective as a substrate for the polyamine transporter than the longer polyamines, such as spermine and spermidine (Byers et al, Am. J. Physiol, 257:C545-C553 (1989)).
IV. Spermidine-Based Anti-Cancer Agents
Chemical compounds composed of a nitrogen mustard alkylating agent covalently linked to spermidine have been found to target tumor cells and DNA (Stark et al, J. Med. Chem., 35:4264-4269 (1992); Cohen et al, J. Chem. Soc. Chem. Commun., 1992:298-300 (1992); and Holley et al, Cancer Res., 52: 4190-4195 (1992)). In the chlorambucil-spermidine conjugate, the nitrogen mustard analogue, chlorambucil, is linked via a metabolically labile amide group and a propylamino spacer group, to the secondary amine of spermidine. Polyamine analogues which contain a nitrogen mustard alkylating group attached to the carbon alpha to the secondary amine are not substrates for the DFMO-inducible polyamine transporter (Stark et al, supra).
The above chlorambucil-spermidine conjugate is highly efficient at producing DNA cross-links compared with chlorambucil per se. However, the biological activity profile of the chlorambucil-spermidine conjugate suggests that this compound is not taken up well by cells. That is, in vivo potency does not reach the level predicted from in vitro studies.
The monoaziridinyl analogues of spermidine, N.sup.1 - and N.sup.8 -aziridinylspermidine (N-(3-aziridinylpropyl)-1,4-diaminobutane and N-(4-aziridinylbutyl)-1,3-diaminopropane have also been shown to be cytotoxic against a variety of cancer cell lines in submicromolar concentrations (Yuan et al, Biochem. Pharmacol., 47:1587-1592 (1994)).
However, the above aziridinyl analogues of spermidine are disadvantageous because they do not cross-link DNA.
V. Additional Polyamine-Aziridine Anti-Cancer Agents
Polyamine-aziridine-linked cyclophosphazenes have been found to show anti-cancer activity (Darcel et al, Anticancer Res., 10:1563-1570 (1990); and Dueymes et al, Int. J. Immunopharmacol., 12:555-560 (1990)). These compounds consist of six-membered N.sub.3 P.sub.3 rings bearing two pairs of aziridine groups bound to a phosphorus and a polyamine, such as spermidine, held in a ring structure with nitrogen-phosphorus bonds.
However, the above polyamine-aziridine-linked cyclophosphazenes are disadvantageous because the advantageous steric and electronic properties of the aziridine and polyamine moieties have been greatly altered.